This is a multicentre open labelled phase I trial evaluating the safety and preliminary efficacy of local decitabine treatment of human papillomavirus (HPV)-induced vulvar intraepithelial neoplasia (VIN) grade 2/3.

The main purpose and primary objective of the study is to determine the recommended phase 2 dose (RP2D) of VTD-101 ointment for the topical treatment of HPV-induced VIN grade 2/3. The RP2D is defined as the dose that is safe, tolerable and effective. Corresponding endpoints are the rate of patients experiencing at least one dose limiting toxicity (DLT) and the rate of patients with clinical complete or partial response (cCR/cPR) according to adapted RECIST criteria.

Secondary objectives are to further characterize the efficacy of topical treatment with VTD-101 ointment, to further evaluate the safety and tolerability of topical treatment with VTD-101 ointment, and to evaluate quality of life (QoL) in patients treated with VTD-101 ointment.

Inclusion Criteria:

1. Having provided written informed consent
2. Women ≥ 18 years of age at the time of signing the written informed consent
3. Women with histologically confirmed vulvar intraepithelial neoplasia (VIN) grade 2 or 3 (also referred to as "high grade VIN" or "high-grade squamous intraepithelial lesions [HSIL]")
4. Uni- or multifocal VIN grade 2 or 3
5. Newly diagnosed or recurrent VIN grade 2 or 3
6. Women who refuse standard therapy, have not responded (or no longer respond) to standard therapy, have not tolerated standard therapy or for whom standard therapy is contraindicated
7. Evidence of HPV-induced etiology of the lesion(s) as indicated by the detection of p16INK4a overexpression as well as high-risk (HR) HPV DNA presence in the lesion(s)
8. Women of childbearing potential (WOCBP) must agree to use one highly effective contraceptive method during the treatment period and for at least 6 months after the last IMP administration
9. Ability of patient to understand the character and individual consequences of the clinical trial
10. In the investigator's judgement, is willing and able to comply with the study protocol

Exclusion Criteria:

1. Evidence for or suspicion of vulvar tumor invasion

2. History of vulvar cancer

3. Previous surgical (except biopsy) or medical procedures of the high-grade VIN within the past 4 weeks prior to treatment start

4. Neutropenia or thrombocytopenia

5. Known allergy or hypersensitivity against decitabine or any of the excipients contained in the formulation

6. Current or prior use of immunosuppressive medication within 14 days (3 months for azathioprine, methotrexate, and tofacitinib) before the first dose of VTD-101 ointment. The following are exceptions to this criterion:

   • Intranasal, inhaled or topical (outside the anogenital area) steroids
   • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
   • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

7. Medical conditions associated with severe immunosuppression (e.g., acquired immune deficiency syndrome [AIDS])

8. Active infection within the anogenital tract (except for HPV)

9. Malignancies within 5 years prior to study inclusion with the exception of malignancies with a negligible risk of metastases or death (5-year OS > 90%) like ductal carcinoma in situ or basalioma

10. Evidence of any other disease, neurologic or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of the study medication, puts the patient at higher risk for treatment-related complications or may affect the interpretation of study results

11. Participation in another interventional clinical study ≤ 4 weeks prior to initiation of study treatment or participation in such a study at the same time as this study

12. Receipt of an investigational drug within 4 weeks prior to initiation of study treatment

13. Pregnancy or breast feeding or planning to become pregnant during the treatment period or during the 6 months following the end of treatment. Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment

14. Women of childbearing potential who are unwilling to agree to remain abstinent (refrain from heterosexual intercourse) or to use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 6 months after the last IMP administration

Other study protocol-defined in-/exclusion criteria could apply.